Microsoft PowerPoint - Fesler.pptxJessica Fesler MD, MEd (MEHP) Cleveland Clinic Epilepsy Center
feslerj@ccf.org @drjesfes
Disclosures None
Recognize and diagnose electroclinical and epilepsy syndromes in the adolescent and adult
Summarize treatment strategies and prognostic implications in these epilepsy syndromes
AGE OF ONSET
West Syndrome • Dravet syndrome • Myoclonic epilepsy in infancy • Epilepsy of infancy with migrating focal seizures • Myoclonic encephalopathy in non-progressive disorders
CHILDHOOD • Epilepsy with myoclonic-atonic seizures • Epilepsy with eyelid myoclonias • Lennox-Gastaut syndrome • Childhood absence epilepsy • Epilepsy with myoclonic absences • Panayiotopoulos syndrome • Childhood occipital epilepsy (Gastaut type) • Photosensitive occipital lobe epilepsy • Childhood epilepsy with centrotemporal spikes • Atypical childhood epilepsy with centrotemporal spikes • Epileptic encephaloapthy with continuous spike-and-wave during sleep • Landau-Keffner Syndrome • Autosomal Dominant nocturnal frontal lobe epilepsy
ADOLESCENT/ADULT • Juvenile absence epilepsy • Juvenile myoclonic epilepsy • Epilepsy with generalized tonic-clonic seizures alone • Autosomal dominant epilepsy with auditory features • Other familial temporal lobe epilepsies
VARIABLE • Reflex epilepsies • Progressive myoclonic
epilepsies • Familial focal epilepsy
Juvenile absence epilepsy (JAE) Juvenile myoclonic epilepsy (JME) Epilepsy with generalized tonic-clonic
seizures alone Progressive myoclonic epilepsies Autosomal dominant epilepsy with auditory
features (ADEAF) Other familial temporal lobe epilepsies Reflex epilepsy
Definitions Generalized seizure “engage or involve networks on
both sides of the brain at the onset”
Epilepsy Syndrome “cluster of features incorporating seizure types, EEG and imaging features that tend to occur together…often has age-dependent features…seizures triggers, diurnal variation, sometimes prognosis…distinctive comorbidities…It may have associated etiologic, prognostic, and treatment implications.”
Never a formal classification of epilepsy syndromes by ILAE
Fisher RS, Cross JH, French JA, et al. Operational classification of seizure types by the International League Against Epilepsy: Position Paper of the ILAE Commission for Classification and Terminology. Epilepsia 2017; 58 (4): 522 – 530
JUVENILE ABSENCE EPILEPSY (JAE)
CASE: 12-year-old healthy boy who presents with first convulsive seizure without aura. He has also had weekly staring episodes over the past year that were treated originally as ADHD.
Primary Generalized Epilepsies (PGE) Idiopathic Generalized Epilepsies (IGE)
Genetic Generalized Epilepsy (GGE)
Onset: around puberty, 8 to 16 years (peak 10-12)
Seizure Types: o Absence seizures predominate but not as frequent as CAE and
not typically triggered by hyperventilation o GTC seizure o Rare myoclonic seizures
Can be inherited (positive family history in 1/3)
JAE Electrical Features Generalized spike wave complexes 3 to 4 Hz
JAE Electrical Features Generalized spike wave complexes 3 to 4 Hz
JUVENILE MYOCLONIC EPILEPSY (JME)
CASE: 16-year-old healthy girl who presents with first convulsive seizure at school after staying up until 3am studying for an exam. On further history you find she has been having morning myoclonic jerks for a while and that she has to close her eyes for flashing lights as they make her feel “jumpy”.
Juvenile Myoclonic Epilepsy Development: normal
Onset: Later adolescence, 12 to 18 years (peak 15)
Seizure Types: o Myoclonic seizures
• Upper extremity prominence, typically extensors • Single or repetitive
o GTC seizures
Can be inherited (positive family history in 1/3)
Sensitivity to light, sleep deprivation, alcohol
Often requires long term treatment
1Panayiotopoulos CP, et al. Absences in juvenile myoclonic epilepsy: a clinical and video-electroencephalographic study. Ann Neurol 1989;25(4): 391 - 397
JME Electrical Features Generalized spike wave complex, often polyspike components
Generalized Polyspikes JME Electrical Features
Photoparoxysmal Response JME Electrical Features
EPILEPSY WITH GENERALIZED TONIC-CLONIC SEIZURES ALONE
CASE: 28-year-old man presents for increasing frequency (now monthly) generalized tonic clonic seizures usually occurring in the morning before work. No myoclonic jerks, photosensitivity, or other seizure types. His paternal grandfather and one of his paternal cousins also has epilepsy.
GTC seizures alone Development: normal
Onset: second decade: 5 to 50 years (peak 15)
Worsens with age
o Less frequent myoclonic or absence
Sensitive to light, sleep deprivation, alcohol
GGE Summary & Genetics
CAE +++ - - Childhood 4 to 10
GABRG2, GABRA1, GABRB3, CACNA1H
JME +/- +++ +++ Late adolescence 12 to 18
EFHC1, GABRA1 BRD/RING3, Cx-36, CACNB4, GABRD, CASR, ME2, SCN1B, EFHC2 CLCN2, BRD2
GTC only +/- +/- +++ Second decade
5 to 50 CLCN2
Risk to first degree relative of GGE patients ~ 7%, but remains a generic prediction.1
1Peljto AL, Barker-Cummings C, Vasoli VM, Leibson CL, Hauser WA, Buchhalter JR, Ottman R. Familial risk of epilepsy: A population-based study. Brain 2014;137:795–805
Take home points GGE Genetic ≠ Inherited
Normal development
typically well-controlled, no neurological deficits
Adult onset is not rare o 28% of GGE have onset after age 201
1Marini C, et al. J Neurol Neurosurg Psychiatry 2003; 74:192-6
Valproate and topiramate have better seizure control than lamotrigine
Valproate better tolerated than topiramate
“valproate should remain the drug of first choice for many patients with generalized and unclassified epilepsies. However, because of known potential adverse effects of valproate during pregnancy, the benefits for seizure control in women of childbearing years should be considered."
Ask the Experts
Ethosuximide in patient with absence only
Levetiracetam in patients with GGE with GTC & myoclonic
2018 AAN / AES Practice Guidelines
Kanner AM, Ashman E, Gloss D et al. Practice guideline update summary: Efficacy and tolerability of the new antiepileptic drugs I: Treatment of new-onset epilepsy. Neurology. 2018; 91 (2)
Generalized Epilepsy Treatment First Line: Valproate (consider teratogenicity)
Second Line: Topiramate, Lamotrigine o Lamotrigine could exacerbate myoclonus level F
Third Line: o Levetiracetam (good for myoclonus) class B o Zonisamide case series
Possibly Effective: Benzodiazepines, Primidone, Phenobarbital
Avoid: (aggravate seizures) class IV2
o Carbamazepine o Oxcarbazepine o Vigabatrin o Gabapentin o Tiagabine o Phenytoin
Glauser T et al. Updated ILAE evidence review of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic syndromes. Epilepsia 2013; 54 (3): 551 – 563. 2Guerrini et al., 1998; Genton, 2000; Somerville, 2009
Long Term Outcome of JME First Author Pub. Year n Outcome
Delgado 1984 43 28%(12) relapse with medication withdrawal after 2 yr seizure free
Camfield 2009 23 17% seizure free at 25 yrs f/u Seneviratne 2012 review < 20% remain in remission without
treatment Geithner 2012 31 68% seizure free at 25-63 yr f/u
Senf 2013 66 59% seizure free > 5 years at 45 yr f/u Hofler 2014 175 8% seizure free > 10 yr
Vonderwulbecke 2017 176 60% > 5 years seizure free at 43 yr f/u
Prognosis of GGE Response to treatment overall good (but not complete)
Previous reports long term remission rates higher in CAE than JAE/JME
Long term seizure outcome hardly differed between the three subsyndromes
60% seizure free 5 years 14% > 10 years seizure free with 5 years off medication
13-year-old developmentally normal teenage boy: - First generalized tonic clonic seizure at age 9 - Myoclonic jerks started age 12 - Absence seizures started at age 8 (not having currently) - Older brother with similar history controlled on medications
What is the best diagnosis?
ABSENCE MYOCLONIC GTC
CAECAE JAEJAE
JMEJME
Same patient returns at age 15 refractory to levetiracetam and zonisamide. He develops unsteady gait and tremor, as well as worsening myoclonus that now occurs for hours and with startle. He begins to have decline in school performance, becoming more withdrawn. What is the diagnosis?
PROGRESSIVE MYOCLONIC EPILEPSY (PME)
similar way Rare Genetic Progressive, neurodegenerative with poor outcome Childhood or adolescence EEG: Slow, generalized spikes and wave 2.5 to 6 Hz,
polyspikes, focal sharp waves Photosensitivity (lower frequency than GGE)
Progressive Myoclonic Epilepsy (PME) Autosomal Recessive
o Unverricht-Lundborg (ULD) CSTB (EPM1)
o Lafora Disease EPM2A, NHLRC1
o Sialidoses NEU1
TPP1 CLN3, CLN5, CLN6
Mitochondrial
MTTK
Shahwan et al. Lancet Neurol 2005 Girard JM et al. Handb Clin Neurol 2013
Unverricht-Lundborg Disease (ULD) Onset: 6 to 18 years, stabilize by 40, can live to 60s Seizures: Stimulus sensitive myoclonus + GTC/absence Other Features:
o Progressive ataxia, dysarthria, intention tremor o Mild dementia (late feature)
Genetics: autosomal recessive, mutation in cystatin B gene (CSTB, previously EPM1) Treatment tips: Phenytoin dramatically worsens ataxia EEG: generalized spikes and polyspikes with photosensitivity MRI: mild cerebellar / brainstem and less often cerebral atrophy
Lafora Bodies Periodic-acid-Schiff (PAS) positive intracellular polyglucosan inclusion body in neurons, heart, skeletal muscle, liver, sweat gland ducts
Shahwan A, Farrell M, Delanty N. Progressive Myoclonic Epilepsies: a Review of Genetic and Therapuetic Aspects. Lancet Neurology 2005; 4: 239-248.
Jeffrey A. Golden & Brian N. Harding. (2004). Developmental Neuropathology. The International Society of Neuropathology.
Lafora Disease Onset: 6 to 19 years, death < 10 years Seizures: GTC, clonic, myoclonic, astatic, atonic, absence,
focal, and occipital seizures; often deteriorate to status Other Features:
o Normal development until onset, isolated febrile or nonfebrile seizures in childhood
o Progressive cognitive decline o Blindness o Ataxia
Genetics: autosomal recessive, generalized polyglucosan storage disorder o EPM2A gene Laforin o EPM2B (NHLRC1) Malin
Diagnosis: skin biopsy, lafora bodies, genetics EEG: low frequency photoparoxysmal response
Neuronal Ceroid Lipofuscinosis (NCL) Onset: varies with 5 subtypes, rapid progression, early death Seizures: + myoclonus, variable Other Features:
o Progressive blindness characterized by retinal degeneration and optic atrophy
o Progressive cognitive decline
Genetics: autosomal recessive (except adult subtype can be dominant) accumulation of lipopigments in lysosomes o PPT1, CLN1, TPP1,CLN3, CLN5, CLN6, MFSD8, CLN8, CTSD,
DNAJC5, CTSF, ATP13A2, GRN, KCTD7
Diagnosis: intracellular inclusions (eccrine, conjunctival, muscle biopsy) or genetics
EEG: Low frequency photic stimulation may induce occipital spikes, giant VEPs
MRI: global atrophy, white matter T2 hyperintensities
NCL Subtypes o Type 2 Late infantile (Jansky-Bielschowsky)
Onset 2.5 to 4 years, death in 5 years
TPP1
o Type 3 Juvenile (Spielmeyer-Vogt-Sjogren or Batten) Onset: 4 to 10 years
Prominent feature is loss of vision, seizures less prmonent
CLN3
o Type 4 Adult (Kuf's or Parry) Onset: adolescence or adulthood
no eye features
o Type 5 Finnish variant late infantile CLN5
o Type 6 Late infantile variant CLN6
Myoclonic Epilepsy with Ragged Red Fibers
Gomori trichrome with ragged red fibers
Shahwan A, et al. Lancet Neurology 2005
Clinical Features:
Myoclonic Epilepsy with Ragged Red Fibers (MERRF)
• Onset: childhood to young adult, insidiously or with metabolic crisis
• Genetics: Mitochondrial (maternal) or autosomal or sporadic tRNA Lys gene (MTTK) mutation
• Diagnosis: Ragged red fibers on muscle biopsy, genetics
• MRI: atrophy and calcificatins of basal ganglia, T2 grey matter intensity changes
• Treatment tips: Caution with valproate, sometimes emprically treated antioxidant vitamins, cofactors (coenzyme Q, L- carnitine)
Heroman JW, Rychwalski P, Barr CC. Cherry Red Spot in Sialidosis (Mucolipidosis Type I). Arch Ophthalmol.2008;126(2):270– 271. doi:10.1001/archophthalmol.2007.31 http://jamanetwork.com/data/Journals/OPHTH/6864/esc70009f1.png
Sialidosis Fundus with Cherry – Red Spot
Sialidosis I Onset: Juvenile Seizures: severe action/intention myoclonus, later GTC Other Features:
o Cherry red spot, progressive visual failure o Gradual ataxia, spasticity o Painful sensory peripheral neuropathy o Dysmorphism: coarse faces, corneal clouding, skeletal dysplasia o Much less cognitive issue
Genetics: autosomal recessive, neuroaminidase A, Nue1 gene
Diagnosis: Vacuolate Kupffer cells, genetics
TYPE II: similar but more severe, as early as neonatal onset, with hepatosplenomegaly and mental deterioration
Dentato-rubral-pallido-luysian atrophy (DRPLA)
Onset: PME phenotype only if onset < age 20 Seizures: myoclonic, GTC Other Features:
o Extrapyramidal symptoms o Dementia
Genetics: autosomal dominant with anticipation, unstable expansion of CAG trinucleotide repeats of DRPLA
MRI: parasaggital atrophy esp. in pons and cerebellum
Summary of common PME Disease Age of
onset Seizures Dementia Ataxia Distinctive
features ULD 6 to 18 Myoclonic ++++
GTC/absence Minimal Late Milder, live to 60s
No PHT!
Lafora 6 to 19 Myoclonic, GTC, atonic, focal ++ occipital (status)
Early and severe
MERRF Child to young adult
Myoclonus +, GTC Variable, typically present
Variable, typically present
Ragged red fibers, can present in metabolic crisis, deafness, DM, myopathy, lipomas No VPA!
Sialidoses Vary, juvenile
Gradual Cherry red spot on fundus, progressive visual failure, dysmorphic
DRPLA < age 20 (for PME)
Myoclonic +, GTC Variable, but present
variable
Adapted portions from Shahwan A, 2005.
Other Rare PME o Gaucher III (glucocerebrosidase deficiency) o SSPE (Subacute Sclerosing Panencephalitis) o Juvenile GM2 gangliosidoses (Taysachs, Sandhoff,
Hexosaminidase A&B deficiency) o Pantothenate kinase-associated neurodegeneration
(Hallervorden-Spatz) o Ataxia-PME disease (PRICKLE1) o Action myoclonus renal failure syndrome (SCARB2) o SCARB2 without renal failure (ULD like) o Neuroserpin mutations
Management of PME
consultation o Genetic testing
Work-up Treatment o Seizure Management
No VPA in MERRF No PHT in ULD LEV for myoclonus Try ZNS, VPA, PHB,
benzodiazepines Avoid: LTG, PHT, CBZ, GBP,
VGB, TGB
o Rehabilitation o Symptomatic, Palliation o Genetic counseling
Autosomal Dominant Partial Epilepsy with Auditory Features Onset: 2 to 60 years (peak teens)1
Isolated auditory auras or many evolve to loss of
consciousness or generalized tonic clonic
Seizure frequency low, can be reflexic
Typically nonlesional MRI
Responsive to treatment (96%)
Genetics: RELN, LGI1 mutations2
1Bisulli et al, Brain 2004 2Michelucci et al, Epilepsy & Behavior, 2017
Other Familial Temporal Lobe Epilepsy
Familial Mesial Temporal Lobe Epilepsy (FMTLE)
o Heterogeneous
o Benign prognosis and good response to meds
o Normal MRI or mesial temporal sclerosis
o Varied genetics, autosomal dominant or recessive
Crompton et al, Brain 2010
Reflex Epilepsy Seizures not spontaneous but precipitated by stimulus
o Should be objective and consistent
ILAE in 1989: “epilepsies characterized by specific modes of seizure precipitation”
Tasks/stimuli activate an area that may be hyperexcitable. If a large enough volume (or network) becomes activated it can reach “critical mass” and result in a seizure.
Generalized or focal
Reflex Epilepsy Types Language or Reading Induced : Often cause jaw jerks or visual symptoms may
progress to GTC, Inherited, onset late puberty, benign, typically no spontaneous seizures
Startle: (sudden unexpected arousal), typically symptomatic to large brain lesions, often injury to sensorimotor and premotor cortex, many delayed
Elementary Visual: (most common), photosensitive, pattern sensitive, eye closure sensitivity idiopathic
photosensitive occipital lobe epilepsy, occipital hyperexcitability Audiogenic: stimulus very specific, can be musicogenic (association with right
temporal?), often also have spontaneous seizures Proprioceptive/Touch: can be active or passive movement, often involves sensorimotor
of contralateral hemisphere
Koepp MJ, et al. Lancet Neurol 2016
HIGH YIELD POINTS
o Young adult with myoclonus, GTC = JME o VPA drug of choice in GGE (teratogen) o LTG may worsen myoclonus, LEV may help o In GGE, no narrow spectrum CBZ, OXC, VGB, GBP, TGB, PHT o PME can look like GGE initially o Myoclonus, seizure, neurological deterioration, ataxia = PME o Occipital epilepsy + PME = Lafora o Mitochondrial + PME = MERRF ; no VPA o Cherry-red-spot + PME = Sialidosis o Mild PME that survives to adult = ULD ; no PHT o ADLTE = LGI1, RELN
References • Wyllie’s Treatment of Epilepsy Principles and Practice. Sixth Edition. 2015. “Topiramate” Chapters 4, 9, 15, 18, 19, 24. • Scheffer IA, Berkovic S, Capovilla G, et al. ILAE classification of the epilepsies Epilepsia 2017. 58 (4): 512 – 521 • Shahwan A, Farrell M, Delanty N. Progressive myoclonic epilepsies: a review of genetic and therapeutic aspects. Lancet
Neurol 2005; 4: 239 – 248. • Ottman R, Hirose S, Jain S, et al. Genetic testing in the epilepsies – report of the ILAE Genetics Commission. Epilepsia
2010; 51 (4): 655 – 670. • Fisher RS, Cross JH, French JA, et al. Operational classification of seizure types by the International League Agains
Epilepsy: Position Paper of the ILAE Commsion for Classification and Terminology. Epilepsia 2017; 58 (4): 522 – 530 • Panayiotopoulos CP, et al. Absences in juvenile myoclonic epilepsy: a clinical and video-electroencephalographic study. Ann
Neurol 1989;25(4): 391 – 397 • Marini C, et al. J Neurol Neurosurg Psychiatry 2003; 74:192-6 • Marson AG, et al. The SANAD study of effectiveness of valproate, lamotrigine, or topiramate for generalized and
unclassifiable epilepsy: an unblinded randomised control trial. Lancet. 2007;369(9566):1016 – 1026 • Shih JJ, Whitlock JB, et al. Epilepsy treatment in adults and adolescents: Expert opinion, 2016. Epilepsy & Behavior 69
(2017) 186 - 122. • Glauser T et al. Updated ILAE evidence review of antiepileptic drug efficacy and effectiveness as initial monotherapy for
epileptic syndromes. Epilepsia 2013; 54 (3): 551 – 563. • Camfield CS, Camfield PR. Juvenile myoclonic epilepsy 25 years after seizure onset: A population-based study. Neurology
2009, 73 (13): 1041 – 1045. • Delgado Escueta AV, Enrile-Bascal F. Juvenile myoclonic epilepsy of janz. Neurology. 1984; 34(3):285 – 294. • Senf P, Schmitz B, Holtkamp M, et al. Prognosis of juvenile myoclonic epilepsy 45 years after onset. Neurology 2013; 81
(24): 2128 – 2133. • Seneviratne U et al. The prognosis of idiopathic genearlized epilepsy. Epilepsia 2012; 53(12):2079–2090 • Höfler J et al. Seizure outcome in 175 patients with juvenile myoclonic epilepsy - A long-term observational study. Epilepsy
Research 2014; 108 (10): 1817 – 1824. • Ottman R, et al. LGI1 mutations in autosomal dominant lateral temporal epilepsy with auditory features Neurology
2004;62:1120 - 1126. • Michelucci R et al. The clinical phenotype of autosomal dominant lateral temporal lobe epilepsy related to reelin mutations.
Epilepsy & Behavior. 2017; 68: 103 -107. • Koepp MJ, Caciagli L, Pressler RM, et al. Refelx seizures, traits, and epilepsies; from physiology to pathology. Lancet
Neurol 2016; 15: 92 – 105. • International League Against Epilepsy Website, https://www.epilepsydiagnosis.org/syndrome/epilepsy-syndrome-
groupoverview.html